Infection with human immunodeficiency virus type 1 (HIV) is characterized by T cell loss and increased risk of illness or death from infection. Since the thymus is the primary site of T cell development, the state of thymic function in an immunodeficient individual may be a pivotal factor in determining the potential for T cell recovery. Although the thymus is generally thought to be active only early in life, evidence suggests that a thymic reserve persists into adulthood and can be summoned in times of need. We previously hypothesized that therapies designed to enhance T lymphopoiesis might facilitate immune restoration. Based upon data from animal studies suggesting growth hormone (GH) enhances thymic function, we conducted a prospective study of 5 adults with HIV infection, and found that GH therapy was associated with reversal of thymic involution and increased circulating naive CD4+ T cells. These results suggest that T cell production may be inducible during immunodeficiency. Despite its clinical promise, mechanisms of GH action remain unclear. GH seemingly acts by reversing processes that underlie thymic involution, yet these processes are not well established. While some data indicate that proliferative defects in hematopoietic progenitor cells (HPCs) contribute significantly to thymic involution, other data suggest that decreased thymic function is due to an inability of the thymic stromal compartment to support the expansion and maturation of HPCs. It is likely that hematopoietic and thymopoietic deficits coexist and that, combined, they are sufficient to impede normal thymopoiesis. Hence, potential immune targets of GH remain broadly defined. The central hypothesis of this proposal is that thymic stromal cells are a primary target of GH effects on thymopoiesis and that GH enhances stromal expression of factors that facilitate the recruitment, migration, survival, or expansion of newly arrived HPCs. These effects could be induced directly by GH, or by its proximal mediator, insulin-like growth factor-1 (IGF-1). The specific aims of this proposal are to 1) Characterize human thymic stromal populations and investigate their functional responses to in vitro treatment with GH and IGF-1 and 2) Investigate in vivo effects of GH and IGF-1 on human thymopoiesis in the SCID-hu Thy/Liv model. The overall objective of this proposal is to identify GH and IGF-1 targets within the central immune system and provide a comprehensive analysis of changes in the human thymus in response to in vivo administration of GH and IGF-1. If successful, this information would be directly applicable to the future development of targeted therapies to enhance T cell production in immunodeficient individuals. [unreadable] [unreadable] [unreadable]